The IFN type I family includes IFNα, IFNβ, IFNδ, IFN1, IFNκ, IFNτ, and IFNω. The predominant forms are IFNα, of which 13 closely related proteins are described in humans, and the single IFNβ. Despite the fact that different IFN type I forms may promote different biological responses, all IFN type I are structurally related (their genes lack introns and are located on the short arm of chromosome 9) and signal through the same receptor subunits (Van Boxel-Dezaire et al., Immunity 2006; 25:361-372).
The interest on the relationship between IFN type I and autoimmune disorders is nowadays increasing, since the signs of its induction, the so-called interferon signature, have been recently reported in patients suffering from different autoimmune diseases (Baccala et al. Immunol Rev 2005; 204:9-26). In fact, due to its immune-modulator effects, IFN type I seems to be involved in several pathogenic pathways of various autoimmune conditions.
The paradigm of IFN type I pathogenic relevance in autoimmunity is systemic lupus erythematosus (SLE). SLE is a chronic disease, characterized by a multi-organ involvement, due to a paradoxical damage of organs caused by autoantibodies directed to self-antigens. The etiology of SLE is complex, involving both genetic and environmental factors. The serum level of IFNα in SLE has been shown to correlate with the severity of the disease (Dall'era et al. Ann Rheum Dis 2005; 64:1692-7). Sjögren's syndrome (SS), also known as sicca syndrome, is a chronic, systemic, autoimmune condition which affects the exocrine glands, particularly the salivary and lachrymal glands. Elevated IFNα activity has also been observed in the serum of patients suffering from this disease. Finally, other conditions such as diabetes, rheumatoid arthritis, scleroderma, vasculitis and autoimmune thyroiditis have also been shown to be associated with high levels of IFNα.
Sedaghat et al. also recently suggested that type 1 IFN may play a role in CD4+ T cells depletion in HIV+ patients as they showed that type 1 IFN affect the steady state of normal CD4+ T cells dynamics by shifting the balance towards Th1 effectors that are short lived cells instead of long-lived memory T cells (Sedaghat et al. J. Virol. 2008, 82(4): 1870-1883). This was confirmed in Mandl et al., where it is suggested to diminish the IFNα production by plasmacytoid dendritic cells to ameliorate the pathological immune activation (Mandl et al. Nat. Med. 2008).
Moreover, administration of IFNα has been reported to exacerbate underlying disease in patients with psoriasis, autoimmune thyroiditis and multiple sclerosis and to induce an SLE like syndrome in patients without a previous history of autoimmune disease.
Therefore, there is a need for an agent that inhibits IFNα activity.
Passive immunization with monoclonal neutralizing antibodies is currently being tested in clinical trials with rontalizumab and sifalimumab for the treatment of SLE. However, said therapy presents the drawbacks of targeting only one subset of the 13 for IFNα and the use of passively administrated monoclonal antibodies can be limited by the induction of anti-drug antibodies. Said anti-drug antibodies may neutralize or otherwise compromise the clinical effect of the drugs and can also be associated with serious adverse events related to cross-reactivity with autologous proteins (De Groot et al. Trends. Immunol. 2007, 28(11)).
The present invention thus provides a method for inhibiting IFNα activity in vivo by administering a therapeutically effective amount of an immunogenic product that allows an active immunization which can break immunological B cell tolerance and generate high titers of polyclonal neutralizing antibodies against IFNα and its use for treating IFNα related conditions.